Haematuria, Proteinuria and Chronic Renal Failure

Procare Group: Wednesday 12 October 2011 @ 19:00

St Heliers Presbyterian Church Community Centre

David Voss ED** BSc MBChB FRACP MRCP(UK) RNZAMC

Renal Physician Eastcare & Waitemata Specialists Centres, Ascot Office Park (Remuera)

Haematuria

Haematuria - macroscopic

• Clots => lower urinary tract origin

• Trauma and UT stones

• Tumour

• Glomerulonephritis

• UTI

• Meatal or perineum irritation

• Contamination from menstrual periods

• Structural: stricture; VUR; RN

• Drugs

– cyclophosphamide

Haemoglobinuria

• Haemoglobulinuria

– Dimer – M. Wt = 34,000

• Protein bound (haptoglobin)

– From intravascular lysis

• Occurs once haptoglobin saturated

– Met-haemoglobulinuria (“Coke colour”)

• Slow nephron transit time

• Acid urine

Myoglobinuria

• Myoglobinuria

– Monomer – M. Wt = 17,000

– Not protein bound

– Readily filtered in glomerulus

• Therefore clears serum rapidly

• Discolours urine

• Rhabdomyolysis

– CK (creatine phosphokinase) levels

Other red urine (1)

• Beet – beta(al)nin (14% of population)

– Not seen in ileostomy patients

– ?colonic absorption

– Worse in:

• Fe deficiency

• Oxalaturia (rhubarb, oysters, chocolate, tea,

spinach)

• Pernicious anaemia induced achlorhydria

• Food dyes

• Porphyria

Other red urine (2)

• Food dyes

• Porphyria

• B12

– In treatment of cyanide poisoning

Detection/diagnosis

• Dipstick

– More sensitive than microscopy

• False positives

– Semen (positive haem reaction)

– Alkaline urine

– Myoglobinuria

• Very dilute urine can haemolyse RBCs

– False negatives

• Excessive vitamin C

– Factitious (rare)

Clues from history

• Vigorous exercise or trauma

• Dysuria and pyuria

• Family history

• Unilateral flank pain

• Prostatic obstructive symptoms

• Bleeding disorders

– The case of anti-coagulants

• Travel

• Sterile pyuria (e.g. Tb; analgesics; IN)

Site/level of haematuria

• Glomerular

– RBC casts

– Proteinuria > 500mg/24 hours

– Dysmorphic RBCs

• Especially acanthocytes

– “Coke” coloured urine

• Non-glomerular

– Lower UT symptoms

– clots

Investigations

• Cytology

– 90% sensitivity for CA bladder

– < 35% for upper UT tumours

• Imaging

– USS

– IVP / IVU

– CT

– MR

– pyelography

Imaging

• CT urogram (radiation dose is high)

– Replaced IVU / IVP

• USS

– Not so good for small urothelial lesions

• MR urography

– Misses smaller lesions and non-

obstructing stones

• Retrograde pyelography

– Similar detection to CT urography

The 40 year-old cut off age

• < 40 year old

– Non-tumour

– Renal origin

– USS

• CT if high risk

• >40 (maybe 45 year old)

– CT urography

Cystoscopy

• In combination with CT urogram

– Excellent screening in combination

• Only method to visualise prostate and

urethra

• Source of bleeding

– And treatment

“No cause found”

• Intermittent?

– How far do we investigate?

• 5-10% of cases

• Hypercalciuria and hyperuricosuria

– Family history

• Rare:

– Schistosomiasis

– Radiation

– AV malformations/fistulae

– Haemorrhagic telangiectasia

– Loin pain syndrome

– Nutcracker syndrome

Follow-up / treatment

• Treat the cause

• No specific treatment for haematuria

per se

• No cause found

– 3 to 6 monthly monitoring

– ?duration

• 3-5 years

Summary – haematuria investigation

• Renal function, MSU, urine microscopy

– Urine RBC morphology

• Quantify proteinuria

– 24 hr; protein-creatinine ratio (PCR); random

• Urinary cytology

• Others: Ca and PO4; SPE; BJ proteinuria;

LFT; ANA, dsDNA; ANCA; Ig; PTH;

complements.

• If < 40 year old renal USS

– otherwise CT urogram

Summary – haematuria referral

• Isolated microscopic

– With symptoms -> urologist

– Painless

• < 40 year old -> renal physician

• > 40 year old => cancer (urologist)

• With proteinuria and/or impaired renal

function

-> Renal physician / nephrologist

Proteinuria

Proteinuria

• Marker of urinary tract inflammation

– Primarily renal in origin

• Glomerulonephritis

• Tubulo-interstitial nephritis

• “Transient contamination”

– Prostatitis

– UTI

• Minor

– Seminal fluid

Proteinuria types or origins

• Isolated

– Glomerular

– Tubular

– Overflow

– Mixed

• Any combination of above (e.g. myeloma)

• Other

– Concurrent haematuria

Glomerular proteinuria

• Serum macromolecular proteins

– Albumin

– Glomerular diseases

– Diabetic nephropathy

– “Benign” causes

• Usually < 2 gram/24 hours proteinuria

• Orthostatic

• Exercise induced

Tubular proteinuria

• Low molecular weight proteins

– Not detected by dipsticks

– Freely filtered

• Usually reabsorbed unless tubular overload or

dysfunction

– β2 microglobulin

– Immunoglobulin light chains

– Retinol protein

– Amino acids

Overflow proteinuria

• Myeloma (most common)

– Immunoglobulin light chains

• Less common causes:

– Lysosomal (a. myelomonocytic leukaemia)

– Myoglobin (rhabdomyolysis)

– Haemoglobin (haemolysis)

Detection of Proteinuria

• Dipstick

– Albuminuria

– Misses tubular proteins

• Laboratory quantification

– Pros and cons

Detection of Proteinuria

• 24-hour versus timed urine collection

– Accuracy of 24 hour collection

– Total urine volume in timed collections

• Untimed urinary protein-creatinine ratio

– Pragmatic

– Reproducible

– Affordable and effective

Quantification

dipstick 24 hour

Trace 150 – 300mg

+ 300 – 1,000mg

++ 1 – 3G

+++ 3 – 10G

++++ > 10G

Quantification

24 hour

collection

mg/L or g/L

(spot urine)

mg/mmol

(PCR)

< 300mg 20 – 30 mg/L 20

500mg 40 mg/L 40

1G 0.6 (600mg/L) 60 – 80

3G 2 G/L 180 – 250

10G 6 G/L 600 – 800

Albumin / ACR

• ACR problems

– 24-hour urine and spot urines do not correlate

well

• Orthostatic proteinuria

• Pragmatically first-am and mid-pm are best times

– Depends upon serum creatinine (denominator)

• Muscular people will have a low value

– Vigorous exercise leads to increased albuminuria

• Wait 24 hours

The risk of proteinuria…

• Meta-analysis of general population

cohort: n = 105,872 (ACR) , plus n =

1,128,310 (dipstick proteinuria); mean

follow-up of 7.9 years (cf. a group with

mean eGFR of 95ml/min/1.73m2 BSA)

– Hazard ratios for all cause mortality

• eGFR 60 1.18 (CI 1.05-1.32)

• eGFR 45 1.57 (CI 1.39-1.78)

• eGFR 15 3.14 (CI 2.30-4.13)

The risk of proteinuria……

• Presence of proteinuria alone -> RR of cardiovascular event = 1.3

• Nat Health and Nutrition Examination Survey cardiovascular death rate (unadjusted):

– Proteinuria <30 6.2 deaths / 1000 person-yr

– Proteinuria 30-299 17.9 deaths / 1000 person-yr

– Proteinuria >300 37.2 deaths / 1000 person-yr

• When adjusted:

– Relative hazard 1.57 (30-299 cf. <30 cohort)

– Relative hazard 1.8 (>300 cf. <30 cohort)

Microalbuminuria

• Associated with LV dysfunction; stroke; MI

• Doubles mortality in DM

– Especially in type I DM

• Indicator of inflammation

– Within renal tissue

– Endothelium

Proteinuria

• Concurrent disease

– Inflammation elsewhere (only → small increase)

• E.g. ACR < 10mg/mmol

– Long-standing poorly controlled hypertension

• Rarely above < 3G per day

– Diabetes mellitus

• Usually concurrent diabetic retinopathy

– Connective tissue diseases

– Medications

When to refer

• Unexplained proteinuria

• Worrisome concurrent diagnosis

– Connective tissue diseases

• Nephrotic

• Concurrent impaired renal function

• >1G per 24 hours

~ spot > 600mg/L

~ PCR > 60mg/mmol (60g/mol)

Investigations

• Renal function, uric acid, Ca and PO4

• FBC; ?LFT

• Serum & urine protein electrophoresis

• Renal ultrasound scan

• Others

– Serology - CT diseases

• Renal biopsy

Management

• Generic

– Cease offending agent(s)

• E.g. Nephrotoxins → interstitial nephritis

– ACEi and/or ARBs

• Type I diabetes mellitus

• Other glomerulonephritides

• Specific

– Immunosuppressives

Management

• Goal is to minimise proteinuria

• General rule:

– Double ACEi or ARB dose

→ 30-50% reduction in proteinuria

• Limitation of ACEi & ARB

– hyperkalaemia – when eGFR < 30

Monitoring and follow-up

• Weekly to monthly during initial

treatment

• Subsequently 3 monthly ....

– Takes 3 months, and up to 2 years to see

maximum benefit of ACEi and ARB dose

changes

Dietary salt and proteinuria

• Anti-proteinuria effects of ACEi and

ARB reduced with high salt diet in

NON-DIABETICS

• therefore in the non-diabetic with

proteinuria

– With good BP (systolic < 130mmHg)

– Should have sodium restricted diet

• 24 hour urine Na < 100mmol.

Summary - proteinuria

• Dipsticks test for ALBUMIN

– Will miss tubular protein and myeloma and

light chain disease

• Spot urine for proteinuria is satisfactory

• ACEi and ARBs for proteinuria

• Consider salt restriction if treatment

failure

• 3-monthly monitoring of progress

• Refer if proteinuria > 1G/24 hours

CKD – Chronic Renal Failure

[Cre

ati

nin

e] s

μ

mo

l/L

GFR ml/min/1.73m2 BSA

20 40 60 80 100 120

20

0

4

00

60

0

80

0

0

20

40

60

80

100

120

140

160

180 16-2

9

30-3

9

40-4

9

50-5

9

60-6

9

70-7

9

80-8

9

90-9

9

Age (years)

eG

FR

(m

L/m

in/1

.73m

2)

0

10

20

30

40

50

60

High Limit

Median

Low Limit

60 mL/min

%<60 mL/min

eGFR deteriorates with age (median eGFR for age – a GUIDE)

AGE (years) Male Female

60 80mL/min/1.73 m2 60mL/min/1.73 m2

65 75mL/min/1.73 m2 55mL/min/1.73 m2

70 70mL/min/1.73 m2 50mL/min/1.73 m2

75 65mL/min/1.73 m2 45mL/min/1.73 m2

80 60mL/min/1.73 m2 40mL/min/1.73 m2

85 55mL/min/1.73 m2 35mL/min/1.73 m2

90 50mL/min/1.73 m2 30mL/min/1.73 m2

CRF stages

Stage Description GFR

(ml/min/1.73m2)

1 Kidney damage with normal or ↑ GFR >= 90

2 Kidney damage with

mild ↓GFR

60 – 89

3 Moderate ↓GFR 30 – 59

4 Severe ↓GFR 15 - 29

5 ESRF < 15

Chronic Renal Failure

• Deterioration rates

– >60 yo

• 0.75 to 1 ml/min per annum • Lindeman RD, et al. Kidney Int, 26:861; 1984.

• In CRD - depends upon aetiology

diabetes > PVD / analgesics > gn / PCK

Avoiding Nephrotoxins

• Common toxins

– Lithium.

– Chemotherapeutic agents.

– NSAIDs; COX-2; allopurinol.

– H2 / proton pump blockers - omeprazole.

– OTC/herbals.

– Fibrates.

Summary – The Management

(1)

• Type 1 and 2 probably the same

(renally)

• ACEI or ARB

– Probably both together (type 1 and 2)

• Good glycaemic control

– HbA1c < 6.5%; certainly <7%

• Good BP control

– BP <125/75

Summary – The Management

(2)

• Minimise proteinuria – ACE and ARB

• Avoid nephrotoxins – NSAID

• Exercise – Ideal weight or at least weight reduction

– Glycaemic control

• Statins in CRF – ?ezetimbe (SHARP trial)

Summary – The Management

(3)

• Aspirin

– Macrovascular disease; IHD

• Folate

– >2mg daily (once CRF)

• Refer when eGFR < 30ml/min (MoH)

– <60ml/min

– Erythropoietin (GFR at 45ml/min)

Medication Dosing

• Renally cleared medications

– Needs dose reduction

• Either dose

• Or frequency

• Avoid nephrotoxins

– NSAIDs vs COX2 inhibitors

• Non-prescription OTC & herbals

– “natural”

Medication Dosing

• Care with combinations

– E.g. NSAIDs and PPI

• Antibiotics

– Penicillins and cephalosporins

• Long courses

– Aminoglycosides

• High trough levels

– Vancomycin

• Long courses and high trough levels

Avoiding Nephrotoxins

• Commonly prescribed nephrotoxins

– lithium

– NSAIDs

– COX-2 inhibitors

– Allopurinol

– Cyclosporine; tacrolimus

– H2 / proton pump blockers

– Fibrates